Selective Vulnerability of Senescent Glioblastoma Cells to BCL-XL Inhibition
Issued Date
2022-06-01
Resource Type
ISSN
15417786
eISSN
15573125
Scopus ID
2-s2.0-85131270300
Pubmed ID
35191501
Journal Title
Molecular Cancer Research
Volume
20
Issue
6
Start Page
938
End Page
948
Rights Holder(s)
SCOPUS
Bibliographic Citation
Molecular Cancer Research Vol.20 No.6 (2022) , 938-948
Suggested Citation
Rahman M., Olson I., Mansour M., Carlstrom L.P., Sutiwisesak R., Saber R., Rajani K., Warrington A.E., Howard A., Schroeder M., Chen S., Decker P.A., Sananikone E.F., Zhu Y., Tchkonia T., Parney I.F., Burma S., Brown D., Rodriguez M., Sarkaria J.N., Kirkland J.L., Burns T.C. Selective Vulnerability of Senescent Glioblastoma Cells to BCL-XL Inhibition. Molecular Cancer Research Vol.20 No.6 (2022) , 938-948. 948. doi:10.1158/1541-7786.MCR-21-0029 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/85820
Title
Selective Vulnerability of Senescent Glioblastoma Cells to BCL-XL Inhibition
Author's Affiliation
Other Contributor(s)
Abstract
Glioblastoma (GBM) is a rapidly fatal malignancy typically treated with radiation and temozolomide (TMZ), an alkylating chemotherapeutic. These cytotoxic therapies cause oxidative stress and DNA damage, yielding a senescent-like state of replicative arrest in surviving tumor cells. Unfortunately, recurrence is inevitable and may be driven by surviving tumor cells eventually escaping senescence. A growing number of so-called “senolytic” drugs have been recently identified that are defined by their ability to selectively eliminate senescent cells. A growing inventory of senolytic drugs is under consideration for several diseases associated with aging, inflammation, DNA damage, as well as cancer. Ablation of senescent tumor cells after radiation and chemotherapy could help mitigate recurrence by decreasing the burden of residual tumor cells at risk of recurrence. This strategy has not been previously explored for GBM. We evaluated a panel of 10 previously described senolytic drugs to determine whether any could exhibit selective activity against human GBM persisting after exposure to radiation or TMZ. Three of the 10 drugs have known activity against BCL-XL and preferentially induced apoptosis in radiated or TMZ-treated glioma. This senolytic activity was observed in 12 of 12 human GBM cell lines. Efficacy could not be replicated with BCL-2 inhibition or senolytic agents acting against other putative senolytic targets. Knockdown of BCL-XL decreased survival of radiated GBM cells, whereas knockdown of BCL-2 or BCL-W yielded no senolytic effect. Implications: These findings imply that molecularly heterogeneous GBM lines share selective senescence-induced BCL-XL dependency increase the significance and translational relevance of the senolytic therapy for latent glioma.